Despite the development of effective topical and systemic antibiotics, invasive wound sepsis and septicemia from pseudomonas aeruginosa remain a problem in seriously burned patients. Emergence and development of drug resistant species of bacteria have defied the control obtained through the regimen of potent antibiotics. In recent years numerous reports of gentamicin resistant gram negative organisms (Shulman, J. A., Terry, P. M. Hough, C. E.: Colonization with a gentamicin resistant pseudomonas aeruginosa pyocine type 5 in a burn unit. J. of Inf. Diseases 124:S18, 1971), especially pseudomonas, have appeared in the literature. (Snelling, C. F. T., Ronald, A. R., Cates, C. Y., et al.; Resistance of gram negative bacilli to gentamicin J. of Inf. Diseases 124:S264, 1971; Chadwick, P: Resistance of pseudomonas aeruginosa to gentamicin. Canadian Med. Assoc. J. 109:585, 1973; Bryan, L. E., Shadrabadi, M. S., Van Denelzen, H. M.: Gentamicin resistance in pseudomonas aeruginosa. R-factor mediated resistance. Antimicrobial Agents and Chemotherapy 6:191, 1974). Although silver sulfadiazine (AgSD), the most promising topical agent in the treatment of burn wound infections in this decade (Fox, Jr., C. L.: A new topical therapy for pseudomonas in burns. Arch. Surg. 96:184, 1968; Fox, Jr., C. L. Rappole, B. W., Stanford, J. W.: Control of pseudomonas infection in burns by silver sulfadiazine. Surg. Gyn. Obstr. 128:1021, 1969), appeared to surmount these problems, pseudomonas infections resistant to silver sulfadiazine treatment have been reported recently in burned patients (Gayle, W. E., Mayhall, C. G., Lamb, A., et al: Resistant enterobacter cloacal in a burn center. The ineffectiveness of silver sulfadiazine. J. of Trauma 18:327, 1978; Heggers, J. P., Robson, M. C.: The emergence of silver sulfadiazine resistant pseudomonas aeruginosa. Burns 5:184, 1978).
Similar occurrence of occasional AgSD resistant pseudomonas infections in patients have been observed in other parts of the world. Several such resistant strains have been obtained and the nature of their resistance studied in an experimental burn model. This investigation revealed an unusual phenomena, namely, normal sensitivity of pseudomonas to AgSD in vitro, but resistance to topical AgSD therapy in infected burn wounds in mice and rats. (Modak, S., Stanford, J. W., Bradshaw W., Fox, Jr., C. L.: Silver sulfadiazine resistant pseudomonas infection in experimental burn wounds. 3rd Intrl. Congr. of Pharma. Treatment of Burns, 1980 (in press) ed. Donati L., Burke, J., Bertelli, A., Italy.)
Comparative studies of the virulence and drug sensitivity of in vivo AgSD sensitive and nonsenstive strains were carried out to investigate the possible mechanism of in vivo resistance. Since all the resistant strains obtained from burn patients appeared to be senstive in vitro, the evaluation of a topical agent for its effectiveness was determined in experimental burn models. Several other antibacterial agents known to be effective in vitro were also ineffective against these strains.
The continued search for an effective topical agent has led to the discovery that a synthetic analogue of nalidixic acid, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinolinecarboxylic acid possesses high antipseudomonas activity in vitro (Ito, A., Hira, K., Inoue, M., et al: In vitro antibacterial activity of AM-715, a new nalidixic acid analog. Antimicrobial Agents and Chemotherapy 17:103, 1980, and French Pat. Nos. 879,106 and 870,576) are effective in controlling AgSD resistant pseudomonas infections in burned mice.